Drug-delivery pump with intelligent control

ABSTRACT

Embodiments of the present invention utilize a closed-loop feedback control system to ensure accurate drug delivery. This control system may, for example, utilize a flow sensor to measure the volume of delivery and an intelligent control algorithm to anticipate and compensate for overdoses and underdoses. Feedback control systems in accordance herewith can be applied to any piston- or plunger-driven pump system utilizing sensors that measure flow directly or indirectly. In some embodiments, adjustments are made based on the flow “tail” that occurs in a piston- or plunger-type pump as relaxation of the plunger material continues to push fluid out of the drug reservoir; this residual flow eventually ceases after the plunger returns to its natural state.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of U.S. Ser. No. 12/858,808, filed onAug. 18, 2010, and also claims priority to, and the benefits of, U.S.Ser. No. 61/704,946, filed on Sep. 24, 2012; the entire disclosures ofthese applications are hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to drug-delivery devices, and inparticular to control of piston- or plunger-driven drug-pump devices foraccurate dosing.

BACKGROUND

Subcutaneous drug delivery is employed for treatment of conditions suchas diabetes, and typically involves modalities such as syringeinjections, pre-filled pen injectors and patient-filled portable insulinpumps. Pre-filled pen injectors provide accurate manual insulin dosingusing, for example, a pre-filled, bubble-free glass cartridge. Since theglass cartridges are bubble-free, the priming process is simple for thepatient. Since the injection is performed manually, however, patientcompliance is a challenge; the patient may not observe proper injectiontiming and/or fail to follow the dosing prescription. Portable insulinpumps can provide fully controlled insulin delivery, improving patientcompliance, and reduced numbers of injections (once every 3 days, forexample) and programmable dosing schedules enhance the patient's qualityof life. Patch pumps with low pump profiles can be attached to thepatient's skin without interfering with daily activities such asincluding showering, sleeping, and exercising. Because these pumps aretypically filled by patients, however, risks arise during the primingprocedure. Improperly primed reservoirs may contain large air bubblesand cause the pump to inject too much air into the subcutaneous tissue,which poses serious safety concerns.

Accordingly, portable pumps with small footprints and pre-filled drugreservoirs can address various problems including those discussed above.One of the challenges for pumps utilizing glass vials as drug reservoirsis to provide controlled and accurate drug delivery. This challenge dueto varying stiction/friction forces between the surface of the plungerand glass vial. Even under the same driving pressure, these variableforces may cause the drug to be delivered at different flow rates forbasal (continuous) delivery. It will also make bolus delivery (i.e.,delivery of a discrete dose over a short time period) unpredictable fromone bolus to the next.

A related problem observed in connection with piston-driven pumps is acharacteristic residual “tailing” of the flow rate—that is, if theamount of fluid expelled is plotted as a function of time, the plot willcontain an asymmetric peak having a steepened front portion and anextended tail portion. This is evident, for example, in manydrug-delivery devices that contain a drug reservoir formed of compliantmaterials. This tailing effect leads to a longer delivery time and, onceagain, inaccuracies in delivery volume.

SUMMARY

Embodiments of the present invention utilize a closed-loop feedbackcontrol system to ensure accurate drug delivery. This control systemmay, for example, utilize a flow sensor to measure the volume ofdelivery and an intelligent control algorithm to anticipate andcompensate for overdoses and underdoses. Feedback control systems inaccordance herewith can be applied to any piston- or plunger-driven pumpsystem (hereafter, collectively, “driven” pumps) utilizing sensors thatmeasure flow directly or indirectly. An advantage to this approach isadaptation of the control algorithm to the pump's output, ultimatelyresulting in extremely accurate drug delivery.

In general overview, a driven pump device in accordance herewithtypically includes a cylindrical vial or cartridge with an outlet, and apiston or plunger movable therein. The piston/plunger divides theinterior of the vial into a front chamber that is filled with liquiddrug and, thus, forms the drug reservoir, and a back chamber thatcontains the pump mechanism that drives the piston. For example, inelectrolytic drug pump devices, the back chamber, or “pump chamber,” maycontain a pair of electrodes and an electrolyte from which, uponapplication of a drive current to the electrodes, electrolysis gasevolves, building up pressure in the chamber that pushes the pistonforward so as to expel drug through the outlet. Other pump mechanisms(e.g., electrochemical, motor-driven, etc.) may also be used.

In general, the drug flow rate of a piston pump device can be regulatedvia the drive force/pressure applied by the pump; for electrolyticallydriven pump devices, for example, this is, in turn, a function of thedrive current. The pump can be operated continuously to dispense drug ata desired steady flow rate, or in a “pulsed” manner (i.e., turning thepump on and off at certain intervals for specific periods of time) todeliver a series of discrete drug volumes. (Which mode of operation isused often depends on the drug regimen. For instance, diabetes patientsusually need a continuous, low “basal” rate of insulin, in addition tohigh-rate, short-duration “bolus” deliveries before or after meals.)Sometimes, frequent small-volume bolus injections are used to provide,on average, a very low basal rate; this is called “discrete basaldelivery.” As explained above, the actual mechanics of piston pumpdevices can undermine the accuracy of drug delivery. One problem is thevariable stiction/friction between the piston and glass vial, which cancause unstable flow rates despite constant drive pressure. Anotherproblem is the compression of the piston (which is usually made of arubber-like material) during pump operation, which results, after thepump has been turned off, in a residual “tail” of drug flow as thepiston relaxes from its compressed state. This tail can be stronglyaffected, in addition, by fluid viscosity, which can vary with theparticular drug composition as well as the temperature atadministration. As a result of this tail, the actual drug volumedelivered is larger than the “set” volume, which is the set flow rateduring pump operation multiplied by the time period of operation

Embodiments of the present invention address these inaccuracies bymeasuring the flow rate of drug (with any suitable flow-rate sensordisposed at the drug reservoir outlet or in a cannula, needle, or otherfluid conduct downstream thereof) and adjusting pump operation basedthereon in real time. For bolus deliveries, the “tail volume” (i.e., thevolume of liquid delivered during the residual tail described above) maybe measured during a priming stage (before drug is injected into thepatient), and the “set volume” decreased such that the sum of tailvolume and set volume equals the desired dosage. Similarly, for discretebasal delivery, the set volume for each pulse is adjusted based on theaverage tail volume of a number of immediately preceding pulses. For“continuous basal delivery” (or simply “continuous delivery”), in whichfluid is dispensed continuously rather than in discrete pulses, theaccumulated delivered volume may be repeatedly for a time window, anddeviations of the measured volume from the target volume (i.e., thetarget flow rate times the length of the time window) are compensatedfor by adjusting the set flow rate for the next time window (typicallybetween upper and lower flow-rate boundaries).

Accordingly, in a first aspect, the invention relates to a drug pumpdevice. In various embodiments, the device comprises a drug reservoir;an exit member for fluidically connecting the reservoir with a druginjection site; a sensor; an electrolysis pump comprising a pump chamberin mechanical communication with the drug reservoir via an interveningdisplacement member, where the electrolysis pump is operable to exert apressure to drive the displacement member toward the exit member andthereby force therethrough fluid in the drug chamber; and controlcircuitry for (i) storing a target delivered volume over a specifiedtime, (ii) operating the electrolysis pump to force fluid from the drugreservoir into the exit member in pulses having a time window defined bya pump-start time when pumping begins and a pump-stop time when the pumpis shut off, the time window corresponding to the target deliveredvolume at a predetermined flow rate, (iii) based on signals receivedfrom the sensor, measuring a volume of fluid through the exit memberresulting from a pulse, the measured volume including a pulse volumethrough the exit member during the pulse and an additional tail volumethrough the exit member after the pulse, and (iv) adjusting the pulsetime window based on the measured pulse volume and tail volume toconform collectively to the target delivered volume. In variousembodiments, the sensor is at least one pressure sensor. In otherembodiments, the sensor is at least one flow sensor, and in still otherembodiments the sensor comprises or consists of at least one flow sensorand at least one pressure sensor.

The target delivered volume may correspond to a single bolus, in whichcase the control circuitry may cause measuring to occur during a primingstage and causing adjustment to occur during a delivery stage.Alternatively, the control circuitry may be configured to cause thetarget delivered volume to be dispensed through the exit member over asequence of time-separated pulses occurring over a time interval; inthese implementations, the control circuitry causes measuring to occurduring a first time interval and causing adjustment to occur during asecond time interval following the first time interval. In someembodiments, adjustment is based on the measured pulse volume and tailvolume from a plurality of pulses. another aspect, the invention relatesto a method of controlling an actual delivery volume of fluid to conformto a target delivery volume in a drug pump device comprising a drugreservoir, an exit member for fluidically connecting the reservoir witha drug injection site, and an electrolysis pump operable to force fluidfrom the drug reservoir into the exit member in pulses each having atime window defined by a pump-start time when pumping begins and apump-stop time when the pump is shut off. The time window corresponds toa target delivered volume at a predetermined flow rate. In variousembodiments, the method comprises measuring a volume of fluid throughthe exit member resulting from a pulse, where the measured volumeincludes (i) a pulse volume through the exit member during the pulse and(ii) an additional tail volume through the exit member after the pulse;and adjusting the pulse time window based on the measured pulse volumeand tail volume to conform collectively to the target delivered volume.The measurement may be made with at least one pressure sensor and/or atleast one flow sensor. In some embodiments the target delivered volumecorresponds to a single bolus, in which case the measuring step occursduring a priming stage and the adjusting step occurs during a deliverystage. In other embodiments the target delivered volume is dispensedthrough the exit member over a sequence of time-separated pulsesoccurring over a time interval, in which case the measuring step occursduring a first time interval and the adjusting step occurs during asecond time interval following the first time interval. Moreover, theadjusting step may be based on the measured pulse volume and tail volumefrom a plurality of pulses.

These and other objects, along with advantages and features of thepresent invention herein disclosed, will become more apparent throughreference to the following description, the accompanying drawings, andthe claims. Furthermore, it is to be understood that the features of thevarious embodiments described herein are not mutually exclusive and canexist in various combinations and permutations. As used herein, the term“substantially” means±10% and, in some embodiments, ±5%. A “measure” or“measurement” may be direct or indirect, i.e., a value derived from adirectly measured value.

DESCRIPTION OF THE DRAWINGS

In the drawings, like reference characters generally refer to the sameparts throughout the different views. Also, the drawings are notnecessarily to scale, with an emphasis instead generally being placedupon illustrating the principles of the invention. In the followingdescription, various embodiments of the present invention are describedwith reference to the following drawings, in which:

FIG. 1 is a block diagram illustrating the various functional componentsof electrolytic drug pump devices in accordance with variousembodiments;

FIGS. 2A and 2B are schematic side views of piston pump devices inaccordance with various embodiments;

FIG. 3 illustrates how repeated, alternating pulses and non-deliveryperiods can be combined to obtain an averaged flow rate equal to atargeted flow;

FIGS. 4A-4E graphically depict operation of an adaptive controlalgorithm for overcoming a flow “tail”;

FIG. 5, like FIG. 3, illustrates an example of discrete basal deliveryachieved by multiple pulse/time deliveries;

FIG. 6 graphically depicts computation and use of average tail volumesin a compensating flow scheme at the priming stage;

FIG. 7 graphically depicts computation and use of average tail volumesin a compensating flow scheme at the delivery stage;

FIG. 8 graphically depicts the operation of an adaptive controlalgorithm for continuous basal delivery;

FIG. 9 graphically depicts the operation of an adaptive controlalgorithm for bolus delivery at the priming stage; and

FIG. 10A graphically depicts the delivery stage of the bolus algorithm;and

FIG. 10B graphically depicts the delivery stage of the bolus algorithmin a situation the bolus volume is small and the peak flow rate neverreaches the maximum dosing rate.

DETAILED DESCRIPTION

1. Pump Architecture

FIG. 1 illustrates, in block diagram form, the main functionalcomponents of a drug pump device 100 in accordance with variousembodiments of the present invention. In general, the pump device 100includes a drug reservoir 102 that interfaces with an electrolysis pump104 via a displaceable member 106. The displaceable member 106 may be,for example, a piston, diaphragm, bladder, or plunger. In use, the drugreservoir 102 is filled with medication in liquid form, and pressuregenerated by the pump 104 moves or expands the displaceable member 106so as to push the liquid drug out of the reservoir 102. A cannula,needle, or other exit member 108 connected to an outlet of the drugreservoir 102 conducts the liquid to an infusion set 109. The infusionset 109 may include a catheter fluidically connected to the cannula 108for delivering the drug to a subcutaneous tissue region. A lancet andassociated insertion mechanism may be used to drive the catheter throughthe skin. Alternatively, the infusion set 109 may include another typeof drug-delivery vehicle, e.g., a sponge or other means facilitatingdrug absorption through the skin surface.

The electrolysis pump 104 generally includes an electrolyte-containingchamber (hereinafter also referred to as the “pump chamber”) and,disposed in the chamber, one or more pairs of electrodes that are drivenby a direct-current power source to break the electrolyte into gaseousproducts. Suitable electrolytes include water and aqueous solutions ofsalts, acids, or alkali, as well as non-aqueous ionic solutions. Theelectrolysis of water is summarized in the following chemical reactions:

-   The net result of these reactions is the production of oxygen and    hydrogen gas, which causes an overall volume expansion of the drug    chamber contents. Gas evolution occurs even in a pressurized    environment (reportedly at pressures of up to 200 MPa, corresponding    to about 30,000 psi). As an alternative (or in addition) to water,    ethanol may be used as an electrolyte, resulting in the evolution of    carbon dioxide and hydrogen gas. Ethanol electrolysis is    advantageous due to its greater efficiency and, consequently, lower    power consumption, compared with water electrolysis. Electrolysis    pumps in accordance with several embodiments are described in detail    further below.

The pressure generated by the drug pump 104 may be regulated via a pumpdriver 110 by a system controller 112 (e.g., a microcontroller). Thecontroller 112 may set the drive current and thereby control the rate ofelectrolysis, which, in turn, determines the pressure. In particular,the amount of gas generated is proportional to the drive currentintegrated over time, and can be calculated using Faraday's law ofelectrolysis. For example, creating two hydrogen and one oxygen moleculefrom water requires four electrons; thus, the amount (measured in moles)of gas generated by electrolysis of water equals the total electricalcharge (i.e., current times time), multiplied by a factor of ¾ (becausethree molecules are generated per four electrons), divided by Faraday'sconstant.

The system controller 112 may execute a drug-delivery protocolprogrammed into the drug pump device 100, and may be responsive to oneor more sensors 113, 114 that measure an operational parameter of thedevice 100, such as the pressure in the pump chamber 104 or the flowrate through (or pressure in) the cannula 108. For example, thecontroller 112 may adjust the current supplied to the electrolysiselectrodes based on the pressure inside the pump chamber to achieve atarget pressure. The target pressure, in turn, may be calculated basedon a desired flow rate, using a known relationship between flow rate andpressure (as determined, e.g., by calibration). Due to the low cost ofpressure sensors (such as, e.g., MEMS sensors as used in the automotiveindustry), this option is particularly advantageous for pumps designedfor quick drug delivery. Indeed, two or more pressure sensors 113 may beplaced in the pump chamber to simultaneously monitor pressure therein;this redundancy provides additional feedback to the controller 112,improves accuracy of information, and serves as a backup in case ofmalfunction one of the sensors. Alternatively, the rate of drug flow outof the reservoir 102 may be measured directly and in real-time, using aflow sensor 114 integrated in the exit member 108 in a conventionalmanner. The total delivered dose can be computed by integrating the flowrate over time, and may serve as a control parameter for theelectrolysis current as described in greater detail below.

In some embodiments, a pressure sensor 113 inside the pump chamber isused in combination with a flow sensor 114 in the cannula to increasethe accuracy and precision of the feedback control loop. The use ofmultiple sensors also ensures that, in case the flow sensor 114 fails,the pressure sensor 113 would be able to detect high drug deliveryrates, and shut the pump 104 down to avoid administration of an overdoseto the patient or damage to the pump device. Conversely, the combinationof flow and pressure sensors 114,113 can also detect a violation in thedrug reservoir 102 if pressure is measured in the pump chamber but noflow is measured in the cannula 108, indicating a potential leak. Ingeneral, the sensors used to measure various pump parameters may beflow, thermal, time of flight, pressure, or other sensors known in theart, and may be fabricated (at least in part) from parylene—abiocompatible, thin-film polymer. The cannula 108 may also include acheck valve 116 that prevents accidental drug delivery and backflow ofliquid into the drug reservoir 112; like the sensor 114, the check valve116 may be made of parylene. In other embodiments, silicon or glass areused in part for the flow sensor 114 and valve 116 construction.

The drug pump device 100 may include electronic circuitry 118 (whichmay, but need not, be integrated with the system controller 112) forconditioning and further processing the sensor signal(s) and,optionally, providing pump status information to a user by means ofLEDs, other visual displays, vibrational signals, or audio signals. Inaddition to controlling the drug pump 104, the controller 112 may beused to control other components of the drug pump system; for example,it may trigger insertion of the lancet and catheter. The systemcontroller 112 may be a microcontroller, i.e., an integrated circuitincluding a processor core, memory (e.g., in the form of flash memory,read-only memory (ROM), and/or random-access memory (RAM)), andinput/output ports. The memory may store firmware that directs operationof the drug pump device. In addition, the device may include read-writesystem memory 120. In certain embodiments, the system controller 112 isa general-purpose microprocessor that communicates with the systemmemory 120. The system memory 120 (or memory that is part of amicrocontroller) may store a drug-delivery protocol in the form ofinstructions executable by the controller 112, which may be loaded intothe memory at the time of manufacturing, or at a later time by datatransfer from a hard drive, flash drive, or other storage device, e.g.,via a USB, Ethernet, or firewire port. In alternative embodiments, thesystem controller 112 comprises analog circuitry designed to perform theintended function.

The pump driver 110, system controller 112, and electronic circuitry 118may be powered, via suitable battery electronics, by a battery 122.Suitable batteries 122 include non-rechargeable lithium batteriesapproximating the size of batteries used in wristwatches, as well asrechargeable Li-ion, lithium polymer, thin-film (e.g., Li-PON),nickel-metal-hydride, and nickel cadmium batteries. Other devices forpowering the drug pump device 100, such as a capacitor, solar cell ormotion-generated energy systems, may be used either in place of thebattery 122 or supplementing a smaller battery. This can be useful incases where the patient needs to keep the drug-delivery device 100 onfor several days or more.

In certain embodiments, the drug pump device 100 includes, as part ofthe electronic circuitry 118 or as a separate component, a signalreceiver 124 (for uni-directional telemetry) or a transmitter/receiver124 (for bi-directional telemetry) that allows the device to becontrolled and/or re-programmed remotely by a wireless handheld device150, such as a customized remote control or a smartphone. In certainembodiments, the handheld device 150 and pump device 100 communicateover a (uni- or bidirectional) infrared (IR) link, which may utilize oneor more inexpensive IR light-emitting diodes and phototransistors astransmitters and receivers, respectively. Communication between the drugpump device 100 and the handheld device 150 may also occur at radiofrequencies (RF), using, e.g., a copper coil antenna as thetransmitter/receiver component 124.

The drug-delivery device 100 may be manually activated, e.g., toggled onand off, by means of a switch integrated into the pump housing. In someembodiments, using the toggle switch or another mechanical releasemechanism, the patient may cause a needle to pierce the enclosure of thedrug reservoir 102 (e.g., the septum of a drug vial, as explained belowwith to FIGS. 2A and 2B) to establish a fluidic connection between thereservoir 102 and the cannula 108; priming of the pump can then begin.During priming, liquid is pumped from the reservoir through the fluidpath, ideally displacing air with liquid up to the tip of the injectionneedle. Coupling insertion of the needle into the reservoir 102 with theactivation of the pump device ensures the integrity of the reservoir102, and thus protects the drug, up to the time when the drug isinjected; this is particularly important for pre-filled drug pumpdevices. Similarly, the lancet and catheter of the infusion set 109 maybe inserted by manually releasing a mechanical insertion mechanism. Insome embodiments, insertion of the lancet and catheter automaticallytriggers electronic activation of a pump, e.g., by closing an electroniccircuit. Alternatively, the pump and/or insertion set may be activatedremotely by wireless commands.

The functional components of drug pump devices as described above may bepackaged and configured in various ways. In certain preferredembodiments, the drug pump device is integrated into a patch adherableto the patient's skin. Suitable adhesive patches are generallyfabricated from a flexible material that conforms to the contours of thepatient's body and attaches via an adhesive on the backside surface thatcontacts a patient's skin. The adhesive may be any material suitable andsafe for application to and removal from human skin. Many versions ofsuch adhesives are known in the art, although utilizing an adhesive withgel-like properties may afford a patient particularly advantageouscomfort and flexibility. The adhesive may be covered with a removablelayer to preclude premature adhesion prior to the intended application.As with commonly available bandages, the removable layer preferably doesnot reduce the adhesion properties of the adhesive when removed. In someembodiments, the drug pump device is of a shape and size suitable forimplantation.

The various components of the drug pump device may be held within ahousing mounted on the skin patch. The device may either be fullyself-contained, or, if implemented as discrete, intercommunicatingmodules, reside within a spatial envelope that is wholly within (i.e.,which does not extend beyond in any direction) the perimeter of thepatch. The housing may provide mechanical integrity and protection ofthe components of the drug pump device 100, and prevent disruption ofthe pump's operation from changes in the external environment (such aspressure changes). The control system components 110, 112, 118, 120, 122may be mounted on a circuit which may be flexible and/or may be anintegral part of the pump housing. In some embodiments, the controlsystem components are integrated with the electrolysis electrodes intoself-contained unit.

Drug pump devices 100 in accordance herewith may be designed for singleor repeated use. Multi-use pumps generally include a one-way check valveand a flow sensor, as described above, in the cannula. Further, the drugreservoir of a multi-use pump may be refillable via a refill port,using, e.g., a standard syringe. In some embodiments, the drug pumpdevice 100 is removed from the patient's skin for re-filling. Thepatient may, for example, place the drug pump device 100 and cartridgecontaining the new drug into a home refill system, where the pump deviceand cartridge may be aligned using, e.g., a press-machine mechanism. Thepatient may then press a button to trigger automatic insertion of aneedle that draws liquid drug from the cartridge to the cannula in orderto activate the electronics and begin priming the pump.

The electrolysis pump 104 and drug reservoir 102 may be arranged withinthe device 100 in different ways, the two most common being apiston-pump configuration, in which the pump chamber and reservoir areformed within an elongated vial and separated by a piston movable alongthe axis of the vial, and the diaphragm-pump configuration, in which thereservoir is disposed on top of the pump chamber and separated therefromby a flexible diaphragm. Both configurations are described in detail inU.S. patent application Ser. No. 13/091,047, filed on Apr. 20, 2011,which is hereby incorporated herein by reference in its entirety.

FIG. 2A schematically illustrates an exemplary piston pump device 200.The pump device 200 includes a cylindrical (or, more generally, tubular)vial 202 with a piston 204 movably positioned therein and anelectrolysis electrode structure 206 mounted to one end. A septum 208may be disposed at the other end to seal the vial 202. Both the piston204 and the septum 208 may be made of an elastomeric polymer material,such as a synthetic or natural rubber; in some embodiments, siliconerubber (i.e., polydiorganosiloxane, e.g., polydimethylsiloxane) is used.The piston 204 separates the interior of the vial 202 into a drugreservoir 210 and a pump chamber 212. In use, a needle 214 pierces theseptum 208 to allow fluid egress from the drug reservoir 210; a cannula(not shown) connected to the needle 214 may conduct the fluid to theinfusion set (not shown). The piston pump device 200 is enclosed in ahousing 216, e.g., made of a hard plastic.

The electrodes 206 may be made of any suitable metal, such as, forexample, platinum, titanium, gold, or copper, and may form a pair ofparallel wires or plates. Alternatively, to improve electrolysisefficiency, the electrodes can have non-traditional shapes. For example,they may be interdigitated, or individually wound up into a spiralconfiguration (and oriented so as to face each other) as illustrated inFIG. 2B. Further, as shown, the electrodes 206 may be embedded in ahydrophilic absorbent material 218 (e.g., a cotton ball) that ensurescontinuous contact with the electrolyte 220. This solves a problemfrequently encountered with conventional electrolysis pumps, in whichthe electrodes are simply submerged in liquid electrolyte: as gaseouselectrolysis products are generated, they push the piston towards theoutlet end of the drug reservoir, thereby increasing the volume of theelectrolysis chamber, which causes a decrease in the level of theelectrolyte. Depending on the orientation of the device, one or bothelectrodes may, as a result, gradually emerge from the electrolyte andbecome surrounded by the gas, eventually forming an open circuit and,thus, causing the electrolysis reaction to cease. This problem can beavoided in various ways, one of which is to surround the electrodes witha hydrophilic absorbent material such as (but not limited to) ahydrogel, cotton ball, sponge, or super-absorbent polymer. Theelectrolyte stays inside the hydrophilic absorbent material, whichefficiently expels the generated gas and keeps the electrodesreplenished with electrolyte.

The vial 202 may be fabricated from a glass, polymer, or other materialsthat are inert with respect to the stability of the drug and,preferably, biocompatible. Polymer vials, e.g., made of polypropylene orparylene, may be suitable for certain drugs that degrade faster when incontact with glass, such as protein drugs. For many other drugs, glassis the preferred material. Glass is commonly used in commerciallyavailable and FDA-approved drug vials and containers from many differentmanufacturers. As a result, there are well-established and approvedprocedures for aseptically filling and storing drugs in glasscontainers, which may accelerate the approval process for drug pumpdevices that protect the drug in a glass container, and avoid the needto rebuild a costly aseptic filling manufacturing line. Using glass forthe reservoir further allows the drug to be in contact with similarmaterials during shipping. Suitable glass materials for the vial may beselected based on the chemical resistance and stability as well as theproperties of the material. For example, to reduce the risk of containerbreakage, type-II or type-III soda-lime glasses or type-I borosilicatematerials may be used.

To enhance chemical resistance and maintain the stability of encloseddrug preparations, the interior surface of the vial may have aspecialized coating. Examples of such coatings include chemicallybonded, invisible, ultrathin layers of silicon dioxide or medical-gradesilicone emulsions. In addition to protecting the chemical integrity ofthe enclosed drugs, coatings such as silicone emulsions may provide forlower and more uniform friction between the piston and vial.

In certain embodiments, the piston pump device 200 is manufactured byfitting a conventional, commercially available glass or polymer drugvial, which may already be validated for aseptic filling, with thepiston 204 and electrolysis pump components. A screw-in needle cassettemay be placed over the septum 208, and a mechanical actuation mechanismmay serve to screw the cassette into the vial 202 such that the cassetteneedle 214 punctures the septum 208 and establishes a connection withthe cannula at the time the patient desires to use the pump. Toaccommodate the electrolysis pump, the vial 202 is, in some embodiments,longer than typical commercially available vials, but maintains allother properties such that validated filling methods and the parametersof existing aseptic filling lines need not be changed. The drug pumpdevice may be furnished with a prefilled vial. If a glass vial is used,the drugs can be stored in the pump device for long-term shelf lifewithout the need to change the labeling on the drug.

FIG. 2B illustrates the pump 200 with a pressure sensor located in thepump chamber 212. Signals from the flow sensor and the pressure sensorare received by programmable circuitry and may be used to regulate pumpoperation as described in detail below.

2. Feedback Control

Closed-loop feedback control in accordance herewith ensures accuratedrug delivery in driven pumps. In one delivery scheme, a pump systemdelivers drug in discrete doses or pulses, resulting in flow rates thatare much lower than the continuous delivery capabilities of the pump.Due to the effect of the stiction of the plunger and glass wall of thecartridge at such a low flow each small discrete dose of drug isgenerated after the plunger is pushed to overcome the stiction force.Each discrete delivery may overshoot to a flow rate higher than atargeted flow rate, followed by an abrupt stop of the plunger movementcausing the flow rate to cease for certain interval. Combining theserepeated, alternating pulses and non-delivery periods results in anaveraged flow rate theoretically equal to the targeted flow rate and theamount of dose volume equal to the volume obtained from continuousdelivery mode. This approach is illustrated in FIG. 3, which shows adiscrete dose mode in which the peak flow rate for each pulse is 500nL/min, the duration for each pulse is 4 min, and the average flow raterepresenting a continuous constant delivery mode is 33.3 nL/min.

The mechanics of actually delivering these discrete doses, however, canresult in inaccuracy (such as an overdose or underdose relative to thedesired target delivery). When electrolysis occurs in anelectrolytically driven plunger pump, pressure builds up behind theplunger, causing it to compress. When electrolysis stops, however, theplunger relaxes from this compressed state. The relaxation of theplunger material continues to push fluid out of the drug reservoir,causing a prolonged “tail” of the flow rate. This residual floweventually ceases after the plunger returns to its natural state. Theflow sensor enables the system to determine the actual dose delivered,triggering a control algorithm (such as an artificial neural network,fuzzy logic, etc.) that accounts for deviations from the target dose. Inother embodiments, a pressure sensor in the pump chamber is used insteadof, or in addition to, the flow sensor, since pressure readings arereadily correlated with the volume of fluid expelled from the reservoir.

FIGS. 4A-4E illustrate the general concept of an adaptive controlalgorithm suitable for addressing this problem. In particular, FIG. 4Ashows an ideal discrete dose of 0.05 U (which deviates from a perfectlyrectangular pulse due to a necessary ramp-up time, which representsproper pump operation and does not vary significantly); FIG. 4B showsthe actual delivered dose with additional volume “tail”; FIG. 4Cillustrates measurement of the tail at 0.02 U, which totals 0.07 Udelivered; the pump stops delivery early at 0.03 U, which accounts forthe unwanted tail of 0.02 U shown in FIG. 4D (i.e., the pulse isadjusted so that the tail volume becomes part of the intended deliveryvolume rather than a deviation therefrom); and FIG. 4E illustratesperformance in accordance with embodiments of the present invention,which results in a delivered dose that accurately tracks the target doseshown in FIG. 4A.

A typical insulin pump should be able to provide bolus and backgroundbasal delivery rates over a wide range in order to serve differentpatients' needs. A prefilled insulin pump in accordance herewith cansuccessfully provide suitable basal and bolus ranges. However, due tothe nature of prefilled cartridge pumps, in particular the varyingfriction between the rubber plunger and glass wall among differentcartridges, delivery accuracies can be compromised if corrections forsuch variation are not made. Thus, a real-time intelligent controlalgorithm may be used to compensate for the variation and maintain avery accurate dosage for both basal and bolus delivery.

Due to the unpredictable interaction between the plunger and glasscartridge of a driven pump, many variables can contribute to dosinginaccuracies. Since an initial stiction (initial static friction) existsbetween the plunger and glass vial, the pump must achieve a minimumpressure before the plunger can move smoothly to deliver a trulycontinuous flow rate. In this situation, only dynamic friction occursbetween plunger and the glass container. On the other hand, the initialstiction (or static friction) may limit the minimum flow rate that thepump can offer and make it very difficult to deliver small amount ofdrug. To deliver at flow rates below this threshold, a discrete deliveryscheme herein termed “discrete basal delivery” may be utilized. In thisscheme, the target flow rate is converted to a target volume delivery ina given time period. Several small pulses of insulin are deliveredthroughout the given time span to achieve the target volume delivery,which fulfills the targeted average flow rate as described in thefollowing equation.

$\begin{matrix}{{{Flow}\mspace{14mu} {Rate}\mspace{14mu} \left( \frac{U}{Hr} \right)} = \frac{{Total}\mspace{14mu} {Delivery}\mspace{14mu} {Volume}\mspace{14mu} (U)}{{Time}\mspace{14mu} ({Hr})}} & (3)\end{matrix}$

In one representative embodiment, the the volume of the tail is measuredfrom the previous few (e.g., three) doses the average is determined. Thesystem controller 112 then adjusts the target volume for the next dosebased on this average. The following equations may used by thecontroller to determine the proper correction.

$\begin{matrix}{V_{Tail\_ Avg} = \frac{\sum\limits_{k = 0}^{n}{V_{Tail}(k)}}{n}} & (1) \\{{V_{set}(n)} = {{V_{target}(n)} - V_{Tail\_ Avg}}} & (2)\end{matrix}$

where V_(Tail) _(—) _(Avg) is the average tail volume, V_(Tail) is theindividual tail volume, V_(set) is the predicted volume to be deliveredexcluding the tail volume, and V_(target) is the the total expectedvolume.

A similar approach may be used for continuous delivery. In particular,after analyzing the pump's previous average delivery during a given timeperiod, the system controller 112 adjusts the overall flow rate (on apulse-by-pulse basis) to correct for the previous delivery error duringthe next time period.

FIG. 5 illustrates an example of discrete basal delivery achieved bymultiple pulse/time deliveries. As shown, there are four bolusdeliveries in an hour and the equivalent flow rate is 33.3 nL/min. Togenerate these small pulses, the pressure in the electrolysis chamber isquickly released at the end of each pulse to accurately obtain thetargeted volume for each small pulse. If the pressure is not promptlyreleased, the high pressure will prevent the pump flow from stopping andresult in a large over-delivery. Meanwhile, due to residual pressureinduced from the plunger/glass interaction and the compliance of theplunger, a “tail” is produced that degrades the accuracy of basaldelivery.

In one embodiment that corrects for these errors, the system controller112 executes an adaptive control algorithm (ACA) during a priming stageand during a delivery stage. At the priming stage, a number n ofpredetermined pulses (e.g., 0.05 U/pulse) is scheduled every t minutes.After reaching the target volume for each pulse, the pressure isreleased and the tail volumes measured. Throughout the priming stage,the system controller 112 (see FIG. 1) collects these tail volumes froma number N_(p) of pulses to determine an average tail volume. Thisaveraged volume is taken into account in adjusting the time width of thesubsequent pulse during the delivery stage. The priming tails areaveraged and stored as V_(tail) _(—) _(prime) _(—) _(avg) for futureusage. is illustrated in FIG. 6, in which N_(p) is the number ofdiscrete basal pulses to be delivered during the priming stage, V_(tail)_(—) _(prime)(_(n)) corresponds to the n^(th) tail volume generated bythe n^(th) pulse in the priming stage, and V_(tail) _(—) _(prime) _(—)_(avg) corresponds to the average tail volume of the discrete pulses inthe priming stage.

At the delivery stage, as illustrated in FIG. 7, the discrete basaltarget volume is adjusted according to the average volume of theprevious n tails. The first discrete basal pulse, Set Volume orV_(set)(_(n)), is established as follows. After the tail volumes fromthe n pulses during the priming stage are averaged, V_(tail) _(—)_(prime) _(—) _(avg) is subtracted from V_(target) (the original targetvolume of the pulse) to give V_(set)(1) (i.e., the adjusted volume forthe pulse). In FIG. 7, V_(pulse) _(—) _(target) is the target volume tobe delivered in each pulse, V_(tail)(n) is the tail volume produced byeach pulse, V_(cumulative) is the actual cumulative volume deliveredover time, and V_(tail) _(—) _(avg) is the average tail of the previousn discrete basal pulses.

For each subsequent discrete basal pulse, the system uses the previous ntail volumes in calculating the average tail volume to be used indetermining the V_(set) for the current discrete basal pulse. Forexample, if there are three discrete pulses delivered during the primingstage (n=3), V_(tail) _(—) _(avg) for the first pulse in the deliverystage corresponds to the average of these three previous tails, which inthis case is the average of these three tail volumes during the primingstage. Next, the value of V_(tail) _(—) _(avg) for the second pulse inthe delivery stage corresponds to the average of the three previoustails. However, the three previous tails are the second and thirddiscrete basal pulses in the priming stage and the first pulse of thedelivery stage. V_(tail) _(—) _(avg) for the third pulse in the deliverystage corresponds to the average of the third tail in the priming stageand the first and second tails of the delivery stage, and so forth.

A special case arises when V_(set) is negative. This means that there isan overdose from a previous delivery such that the next scheduled pulseshould deliver a negative volume to achieve the desired target volume,V_(target) _(—) _(overall). Of course, drug pumps ordinarily cannotoperate to withdraw fluid from the patient. Instead, the system setsV_(set) to 0, which causes the controller 112 to skip the pulse in aneffort to correct for a previous over-delivery and achieve the correctoverall target volume, V_(target) _(—) _(overall), Also, to reduce anyover-delivery caused by missing multiple pulses, the system can set amaximum tolerance volume to be delivered at each pulse (V_(max) _(—)_(tor)). The V_(set) volume never exceeds V_(max) _(—) _(tot). If itdoes, the system controller 112 will coerce V_(set) to be equal toV_(max) _(—) _(tor). This ensures overall profile stability, and alsoensures the absence of dramatic change in overdose and underdose causedby frequent over-delivery and missed pulses.

It should be noted that the tail volume can vary over the lifetime ofthe pump or even during an operating cycle based on various factors.Accordingly, calibration is typically performed periodically ratherthan, for example, a single time when the pump is first used. Forexample, the response of an electrolysis-driven pump to a given inputcurrent supplied to the electrolysis electrodes depends on how muchliquid is remaining in the drug reservoir and the gas/liquid ratio inthe electrolysis chamber. Other factors can cause the response of thepump to change over time including, for example, degradation ofelectrolysis electrodes, changes in the concentration of the electrolytein the electrolysis chamber, changes in the flow characteristics ofvalves in the fluid path, and restrictions that form at the exit portdue to tissue growth or some other mechanism.

Similar to discrete basal delivery, continuous basal delivery faceschallenges due to the plunger and glass-wall friction. Ordinarily it isnot necessary to deliver a pulse pattern in continuous basal delivery(as contrasted with discrete basal delivery), and during continuouspumping, the plunger operates above its stiction range. Nonetheless, acontinuous adaptive control algorithm can increase the accuracy of drugdelivery by minimizing the errors caused by interaction between theplunger and the glass wall.

In one embodiment, a continuous adaptive control routine continuouslymonitors the accumulated volume and its deviation from the targetvolume. The routine sets a time window, ΔT, and maximum tolerable flowrate range, ΔQ_(max) _(—) _(tor). The routine calculates the actualvolume delivered during ΔT and its deviation from the target volume.Based on the deviation, a target flow rate, Q_(set)(2), for the next ΔTwindow is determined in order to compensate for the error in deliveryduring the first ΔT window. The maximum tolerance, ΔQ_(max) _(—) _(tor),comes into play when there is too much error in delivery during thefirst ΔT and Q_(set)(2) has been raised or decreased beyond thephysiological range from Q_(set) _(—) _(initial). In such case,Q_(set)(2) is coerced to equal Q_(set) _(—) _(initial)±ΔQ_(max) _(—)_(tor), depending on the delivery error during previous sampling time.This process repeats throughout continuous basal delivery to ensure theoverall stability of the flow profile and delivery accuracy.

There are many ways to raise the Q_(set) for the next AT time window. Asimple example is to have only three possible values for Q_(set):Q_(set) _(—) _(initial), Q_(set) _(—) _(initial)+ΔQ_(max) _(—) _(tor),and Q_(set) _(—) _(min)−ΔQ_(max) _(—) _(tor), In one embodiment, if thecumulative delivered volume did not deviate from the cumulative targetvolume by more than an acceptable percentage (e.g., 5%) at the end ofthe sampling period ΔT, then the system will set Q_(set) to Q_(set) _(—)_(initial), which is the initial flow-rate set point. If the actualdelivered volume exceeds the target volume by more than the acceptablepercentage (e.g., 5%), Q_(set) is set to Q_(set)−ΔQ_(max) _(—) _(tor)for the next time window ΔT. If the actual delivered volume falls belowthe target volume by more than the acceptable percentage (e.g., 5%),Q_(set) is set to Q_(set)+ΔQ_(max) _(—) _(tor) for the next time windowΔT.

In another embodiment, illustrated in FIG. 8, a continuous spectrum ofQ_(set)(n) values is used. In the figure, ΔT is a predefined timewindow, Q_(set)(n) is the target flow rate during the time window,Q_(set) _(—) _(initial) is the initial target flow rate (which is alsoequal to Q_(set), the overall target flow rate), V_(cumulative) is theactual cumulative volume delivered over time, and V_(target) is thetarget cumulative volume over time, % error represents the errorpercentage (i.e., the deviation from V_(target)) by volume, and ΔQ_(max)_(—) _(tor) is the maximum flow rate that Q_(set) cannot exceed.

Each Q_(set)(n) value inversely corresponds to a percentage deviationabove or below the target delivery volume from the previous samplingperiod. If the cumulative delivered volume exceeds the cumulative targetvolume by more than an acceptable percentage (% error), Q_(set)(n) isset to Q_(set) _(—) _(initial)−% error×ΔQ_(max) _(—) _(tor) for the nexttime window ΔT. If the actual delivered volume falls below the targetvolume by more than % error, Q_(set)(n) is set to Q_(set) _(—)_(initial)+% error×ΔQ_(max) _(—) _(tor) for the next time window ΔT.Once again, the Q_(set)(n) can never go below Q_(set) _(—)_(initial)−ΔQ_(max) _(—) _(tor) or above Q_(set) _(—)_(initial)+ΔQ_(max) _(—) _(tor), or the system will coerce theQ_(set)(n) to be set at Q_(set) _(—) _(initial)−ΔQ_(max) _(—) _(tor) orQ_(set) _(—) _(initial)+ΔQ_(max) _(—) _(tor).

More generally, various algorithms and controllers can be used to adjustpump operation through monitoring and adjustment during time windows.During a time window, for example, a closed-loop control scheme, such asproportional-integral-derivative (“PID”) controller, on-off controller,fuzzy logic controller, proportional controller, and/or linearcontroller can be applied maintain as constant a target deliveryparameter such as flow rate. In the next time window, the constanttarget delivery parameter can be altered based on the comparison resultfrom the previous time window For example, a PID controller may be usedduring a timing interval, while a different algorithm, such as the ACA,may be used between time windows to alter the PID controller settings(e.g., the constant target delivery flow rate, the acceptable upper andlower ranges of flow rates, and constants for positional, integral, andderivative calculations). Accordingly, parameters that can be monitoredand adjusted include flow rate, pressure, volume, current, and voltage.Moreover, the integration or differentiation of any one or more of theseparameters may be monitored and adjusted.

Bolus delivery faces the same accuracy challenges caused by the tailvolume as the discrete basal pulses. However, boluses are delivered ondemand, and the accuracy of each individual bolus cannot be compensatedby another bolus. In the case of insulin delivery, boluses are usuallypreceded and followed by a background basal delivery; for example, abolus may be administered just before mealtime, after which insulin isdelivered at the background basal rate until the next bolus. In suchapplications the bolus adaptive control algorithm can be relativelysimple, as it may be based solely on tail volume to achieve overallaccuracy. In other scenarios, however, the flow profile may be morecomplex and/or unpredictable; for example, the rate of drugadministration may be varied periodically or continuously based on themonitored value of a physiologic, environmental or blood-borne chemicalconcentration parameter.

In one embodiment, the real-time bolus adaptive control algorithminvolves a priming stage and a delivery stage. During the priming stage,a bolus (e.g., 1 U) is delivered and the tail volume is measured untilthe flow rate reaches zero. This bolus is sufficient in volume to allowthe system to pump the flow rate up to its maximum dosing rate (e.g., 30U/Hr for insulin pump). If the user selects a smaller bolus volume, thepeak bolus flow rate may never reach the maximum dosing rate (e.g., 30U/Hr). If the user selects a large bolus volume, the peak bolus targetflow rate can be kept at the maximum dosing rate (e.g., 30 U/Hr) using aflow-sensor-based closed-loop control system as described, for example,in copending application Ser. No. 13/680,828, filed on Nov. 19, 2012(the entire disclosure of which is hereby incorporated by reference); itsimply takes longer to finish the bolus.

Operation during the priming stage is illustrated in FIG. 9. The whiterectangle represents V_(set) _(—) _(prime), i.e., the desired volume tobe delivered. Additional flow during ramp-up (V_(rise) _(—) _(prime))and during the tail (V_(tail) _(—) _(prime)) is modeled by fitted curvesQ_(fit) _(—) _(Rise)(t) (flow rate vs. time during the ramp up stage)and Q_(fit) _(—) _(Rise)(t) (representing the tail after V_(set) _(—)_(prime) has completed). The areas under these fitted curves correspondto V_(rise) _(—) _(prime) (the volume delivered during ramp-up) andV_(tail) _(—) _(prime) (the volume delivered during the tail segment).After obtaining the tail volume information and its curve, interpolationcan be used to predict the tail volume for different boluses withdifferent potential peak flow rates. The interpolated curve and the peakflow rate at the end of the bolus can be used to predict the tailvolume.

Two delivery-stage scenarios are illustrated, respectively, in FIGS. 10Aand 10B. In FIG. 10A, the flow pattern corresponds to that shown in FIG.9, with a peak flow rate is that is substantially constant (flat). Acalibrated tail volume V_(tail) _(—) _(avg) _(—) _(calib) is used tocalculate the actual delivery bolus volume, which is equal to thedifference between the target volume V_(target) and the total predictedtail volume (including the background basal cumulative volume); thus,the calibrated set volume V_(set) _(—) _(calib) is equal toV_(target)−V_(tail) _(—) _(avg) _(—) _(calib)−V_(BkgndBasal). The totalbolus volume V_(total) actually delivered is equal to V_(set) _(—)_(calib)+V _(tail) _(—) _(calib), where V_(tail) _(—) _(calib) is theactual run-time tail volume (this time ignoring the background basalcumulative volume).

If the bolus volume is small and the peak flow rate never reaches themaximum dosing rate (e.g., 30 U/Hr) before the target bolus volume hasbeen delivered, a curve-fitting technique may be used to predict thepeak flow rate as illustrated in FIG. 10B; here the tail volume isestimated between the predicted peak flow rate and the (actual)background basal flow rate. This can give a very accurate prediction ofthe tail volume, and during the actual delivery this is used tocompensate for the effect of the tail effect. In FIG. 10B, T₀ is thebolus start time; T_(Qpeak) is the time at which the bolus reaches themaximum peak set flow rate Q_(peak); ΔT is an adjustment time set tocreate a fitted curve as shown in FIG. 10B (and may range from, e.g., 1ms to 1 s depending on the application in order to balance acceptableerror and power restrictions that determine the sample rate and, inturn, the duration of the sample time interval); T₁ is the time whenQ_(tail) _(—) _(calib)(t) (the fitted tail curve) reaches Q_(tail) _(—)_(calib)×(T_(Qpeak)−ΔT); T₂ is the time when Q_(tail) _(—) _(calib)(t)reaches Q_(tail) _(—) _(calib)×(T_(Qpeak)−2ΔT); and T_(BkgndBasal) isthe time when Q_(tail) _(—) _(calib)(t) reaches the background basalflow rate.

After delivery is complete, the tail volume is stored in memory alongwith the estimated (fitted) curve. This historical tail behavior may beused to predict the tail volume for future boluses delivered from thesame cartridge.

As discussed above, the priming stage is typically employed to evacuateair from the fluid path of the device, preventing air and/or debris frombeing injected into the target site, and also wets any sensors in thefluid path. Because of the faults that priming is designed to remediate,calibrating during the priming stage may not be ideal. In someembodiments, therefore, a non-therapeutic dose is dispensed by the pumpfollowing priming, and this dose is used instead of or in addition tothe priming stage for calibration purposes. For example, it may benecessary to use the non-therapeutic dose for calibration if the sensorused therefor is in the fluid path and must be wet to operate properly.As used herein, the term “non-therapeutic dose” means a volume of drugless than a therapeutic dose, and in some embodiments, a dose smallenough to avoid any therapeutic effect or clinically significant effect.

It should be emphasized that, although the preceding discussion hasfocused on a single target dosage, this need not be the case. Manymedications, including monoclonal antibodies, require dosages based onthe patient's weight or the severity of the diseases. Accordingly, pumpsin accordance herewith may have the ability to deliver a range of targetdosages; in some embodiments, a dose-selection mechanism isincorporated—for example, a dose-selection interface may allow the userto select the dosage, which is programmed into memory within thecontroller 112. This interface may be or include a switch, dial,buttons, touch screen, or a variety of user-interface components. Thedosage may also be pre-set by the manufacturer, clinician, pharmacist,or other non-patient entity, and locked for security purposes.

Certain embodiments of the present invention were described above. Itis, however, expressly noted that the present invention is not limitedto those embodiments, but rather the intention is that additions andmodifications to what was expressly described herein are also includedwithin the scope of the invention. Moreover, it is to be understood thatthe features of the various embodiments described herein were notmutually exclusive and can exist in various combinations andpermutations, even if such combinations or permutations were not madeexpress herein, without departing from the spirit and scope of theinvention. In fact, variations, modifications, and other implementationsof what was described herein will occur to those of ordinary skill inthe art without departing from the spirit and the scope of theinvention. As such, the invention is not to be defined only by thepreceding illustrative description.

What is claimed is:
 1. A drug pump device comprising: a drug reservoir;an exit member for fluidically connecting the reservoir with a druginjection site; a sensor; an electrolysis pump comprising a pump chamberin mechanical communication with the drug reservoir via an interveningdisplacement member, the electrolysis pump being operable to exert apressure to drive the displacement member toward the exit member andthereby force therethrough fluid in the drug chamber; and controlcircuitry for (i) storing a target delivered volume over a specifiedtime, (ii) operating the electrolysis pump to force fluid from the drugreservoir into the exit member in pulses having a time window defined bya pump-start time when pumping begins and a pump-stop time when the pumpis shut off, the time window corresponding to the target deliveredvolume at a predetermined flow rate, (iii) based on signals receivedfrom the sensor, measuring a volume of fluid through the exit memberresulting from a pulse, the measured volume including a pulse volumethrough the exit member during the pulse and an additional tail volumethrough the exit member after the pulse, and (iv) adjusting the pulsetime window based on the measured pulse volume and tail volume toconform collectively to the target delivered volume.
 2. The device ofclaim 1, wherein the sensor is at least one pressure sensor.
 3. Thedevice of claim 1, wherein the sensor is at least one flow sensor. 4.The device of claim 1, wherein the sensor comprises at least one flowsensor and at least one pressure sensor.
 5. The device of claim 1,wherein the target delivered volume corresponds to a single bolus, thecontrol circuitry causing measuring to occur during a priming stage andcausing adjustment to occur during a delivery stage.
 6. The device ofclaim 1, wherein the control circuitry causes the target deliveredvolume to be dispensed through the exit member over a sequence oftime-separated pulses occurring over a time interval, the controlcircuitry causing measuring to occur during a first time interval andcausing adjustment to occur during a second time interval following thefirst time interval.
 7. The device of claim 6, wherein the adjustment isbased on the measured pulse volume and tail volume from a plurality ofpulses.
 8. In a drug pump device comprising a drug reservoir, an exitmember for fluidically connecting the reservoir with a drug injectionsite, and an electrolysis pump operable to force fluid from the drugreservoir into the exit member in pulses each having a time windowdefined by a pump-start time when pumping begins and a pump-stop timewhen the pump is shut off, the time window corresponding to a targetdelivered volume at a predetermined flow rate, a method of controllingan actual delivery volume of fluid to conform to a target deliveryvolume, the method comprising: measuring a volume of fluid through theexit member resulting from a pulse, the measured volume including (i) apulse volume through the exit member during the pulse and (ii) anadditional tail volume through the exit member after the pulse; andadjusting the pulse time window based on the measured pulse volume andtail volume to conform collectively to the target delivered volume. 9.The method of claim 8, wherein the measurement is made with at least onepressure sensor.
 10. The method of claim 8, wherein the sensor is atleast one flow sensor.
 11. The method of claim 8, wherein the targetdelivered volume corresponds to a single bolus, the measuring stepoccurring during a priming stage and the adjusting step occurring duringa delivery stage.
 12. The method of claim 8, wherein the targetdelivered volume is dispensed through the exit member over a sequence oftime-separated pulses occurring over a time interval, the measuring stepoccurring during a first time interval and the adjusting step occurringduring a second time interval following the first time interval.
 13. Themethod of claim 12, wherein the adjusting step is based on the measuredpulse volume and tail volume from a plurality of pulses.